Small molecule inhibitor of tau self-association in a mouse model of tauopathy: A preventive study in P301L tau JNPL3 mice

Advances in tau biology and the difficulties of amyloid-directed immunotherapeutics have heightened interest in tau as a target for small molecule drug discovery for neurodegenerative diseases. Here, we evaluated OLX-07010, a small molecule inhibitor of tau self-association, for the prevention of tau aggregation. The primary endpoint of the study was statistically significant reduction of insoluble tau aggregates in treated JNPL3 mice compared with Vehicle-control mice. Secondary endpoints were dose-dependent reduction of insoluble tau aggregates, reduction of phosphorylated tau, and reduction of soluble tau. This study was performed in JNPL3 mice, which are representative of inherited forms of 4-repeat tauopathies with the P301L tau mutation (eg, progressive supranuclear palsy and frontotemporal dementia). The P301L mutation makes tau prone to aggregation; therefore, JNPL3 mice present a more challenging target than mouse models of human tau without mutations. JNPL3 mice were treated f..., The blinded study was independently performed by Peter Davies, Ph.D. and the datasets were provided to Oligomerix which unblinded the study groups., The data for each figure are provided in an Excel Spreadsheet using one sheet per figure (1-8).
Each set of data includes the results for the Baseline, Vehicle and 30 and 40 mg/kg Treatment Groups.
No outliers were removed from these data. Most of the data are results from ELISAs, and some are from immunoblots or LC-MS/MS analyses of compound in serum.Â

tau蛋白（tau）生物学研究的进展，以及靶向淀粉样蛋白的免疫治疗所面临的诸多困境，使得学界将tau蛋白作为神经退行性疾病小分子药物研发靶点的研究兴趣显著提升。本研究评估了OLX-07010——一种靶向tau蛋白自聚集的小分子抑制剂——在预防tau蛋白聚集方面的效果。本研究的主要终点为：与溶媒对照组小鼠相比，给药后的JNPL3小鼠体内不溶性tau蛋白聚集物水平出现具有统计学意义的降低。次要终点包括：不溶性tau蛋白聚集物水平呈剂量依赖性降低、磷酸化tau蛋白水平降低，以及可溶性tau蛋白水平降低。本研究使用的JNPL3小鼠，是携带P301L tau突变的4次重复tau蛋白病（4-repeat tauopathies）遗传性模型的代表，该类疾病包括进行性核上性麻痹和额颞叶痴呆。P301L突变会使tau蛋白更易发生聚集，因此相较于携带野生型人tau蛋白的小鼠模型，JNPL3小鼠是更具挑战性的研究对象。JNPL3小鼠经[原文此处内容截断]给药；本盲法研究由Peter Davies博士独立完成，数据集提交至Oligomerix公司后由该公司完成研究分组揭盲。每张图（共1-8号）的数据均以Excel电子表格形式提供，每个图对应一个工作表。每组数据均包含基线组、溶媒对照组以及30mg/kg、40mg/kg给药组的实验结果。本数据集未剔除任何异常值。绝大多数数据为酶联免疫吸附实验（ELISA）结果，其余部分来自免疫印迹实验或血清中化合物的液相色谱-串联质谱（LC-MS/MS）分析结果。